Antidepressants, Part 1: 100 Years and Counting: Page 2 of 5

Table 3. Additional FDA-approved indications for at least one antidepressant

Table 4. Four steps of the STAR*D algorithm

MDD has haunted human civilization throughout recorded history and has likely been a companion of humanity from our earliest evolutionary roots. Over the millennia, a major depressive episode has been explained by far-ranging and contradictory theories, including demonic possession, a conflict of our “soul” with our earthly body, childhood developmental dysfunction, hormonal imbalance, a symptom of a primary illness of the body, bad luck from our genetic lottery, a narcissistic injury to our ego structure, the outcome of a structural abnormality of our brain, or the result of ingestion of a substance of abuse or some other toxin —just to name a few. What is clear is that MDD is all too common; DSM-5 reports that it will affect approximately 7% of individuals in the US.

Depression: one of humanity’s greatest burdens

Despite its pervasive presence across cultures and time, depression continues to be under-recognized and undertreated. It remains one of the most common causes of disability worldwide and is a significant risk factor for suicide —which is currently the 10th most common cause of death in the US according to the CDC.

Treatments abound, and some individuals respond dramatically to a wide range of treatment options (Table 1). However, in the practice of medicine, especially in the subspecialty of psychiatry, complete remission of a depressive episode can be quite challenging to achieve. When we select an antidepressant to treat an episode of MDD, either as a primary modality or in addition to other complementary interventions, we have many medications to choose from; however, there is no clear first-line drug. Despite many antidepressants in our arsenal (Table 2), findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study suggest that only 49% of depressed patients have a 50% improvement in their depression with citalopram and only 37% achieve remission of symptoms.1,2 Earlier case studies showed that roughly 30% of individuals achieve remission.3

Some critics have argued that antidepressants work no better than a placebo; however, the extensive evidence-based literature consistently demonstrates the efficacy of antidepressants. Although there is no “magic bullet,” mental health workers on an in-patient psychiatric unit will tell you that antidepressants are effective and, at times, lifesaving. There has also been criticism that antidepressants are overprescribed, citing the increase in prescriptions for antidepressants documented in large insurance company databases. These data are flawed, as the term “antidepressant” erroneously implies that these medications are only being used to treat depression.

Although rooted in the initial use of these drugs —to treat depression —there are many other indications, both FDA-approved and off-label, for which antidepressants are used as first- or second-line treatment (Table 3). A detailed review of the national patterns of antidepressant prescribing in the US reported that from 1996 to 2005, the rate of antidepressant use increased from 5.84% to 10.12%.4 The researchers concluded that part of this increase in antidepressant prescribing resulted from their use to treat anxiety disorders, bipolar disorder, and sleep-related disorders. In addition, they noted that during the study period several antidepressants were FDA-approved for anxiety disorders, and clinical guidelines were published that supported the use of some antidepressants for anxiety disorders as well as other conditions.

Considering our understanding of the neurobiology of depression and treatment options that existed a mere 100 years ago, and the knowledge and treatments that are currently available, psychiatry should be quite proud of the progress made. However, regarding the development of newer antidepressants, we have been immobilized in the comfortable and seductive monoamine hypothesis of depression. Fortunately, a new layer of the metaphorical onion has been peeled away, and the future holds promise of treatments with novel mechanisms of action. The treatment of depression should include all modalities available to us (Table 1).